Preparation of 1-substituted-3-chloropyrrolidines

ABSTRACT

A method for preparing a 1-hydrocarbyl-3-chloropyrrolidine, particularly, a method of preparing said pyrrolidine by rearrangement of an N-chloro-1-hydrocarbyl-amino-2-chlorobutane to a 1-hydrocarbyl-amino-2,4-dichlorobutane, which then is cyclized. This rearrangement is carried out by treatment of the 2-chlorobutane by treatment with a strongly ionized acid and a free radical generating catalyst. The intermediate dichlorobutane then is cyclized to the chloropyrrolidine by means of treatment with a base. The invention is also concerned with novel compositions including 1-hydrocarbyl-amino-2-chlorobutanes, Nchloro-1-hydrocarbyl-amino-2-chlorobutanes and 1-hydrocarbylamino-2,4-dichlorobutanes.

United States atent Brown et al.

[ 51 Sept. 12, 1972 PREPARATION OF l-SUBSTlTUTED-3- CHLOROPYRROLIDINES[22] Filed: Dec. 17, 1970 [21] Appl. No.: 99,252

Related US. Application Data [63] Continuation-impart of Ser. No.746,284, July 22, 1968, abandoned.

[52] US. Cl. ..260/326.8, 260/570.8 R, 260/578, 2601583 G, 260/999 [51]Int. Cl. ..C07d 27/04 [58] Field of Search ..260/326.8

[56] References Cited UNITED STATES PATENTS 3,318,908 5/1967 Swidinskyet al. ....260/326.62

Primary ExaminerAlex Mazel Assistant Examiner-Joseph A. NarcavageAttorneyFrank E. Robbins, Joseph Shekleton, Janet E. Price, Robert D.Weist, Martha A. Michaels and Dorothy R. Thumler [5 7] ABSTRACT A methodfor preparing a l-hydrocarbyl-3-chloropyrrolidine, particularly, amethod of preparing said pyrrolidine by rearrangement of anN-chloro-l-hydrocarbyl-amino-Z-chlorobutane to a l-hydrocarbyl-amino-2,4-dichlorobutane, which then is cyclized. This rearrangement iscarried out by treatment of the 2- chlorobutane by treatment with astrongly ionized acid and a free radical generating catalyst. Theintermediate dichlorobutane then is cyclized to the chloropyrrolidine bymeans of treatment with a base. The invention is also concerned withnovel compositions including l-hydrocarbyl-amino-2-chlorobutanes,N-chloro- 1 -hydrocarbyl-amino-2-chlorobutanes and lhydrocarbyl-amino-Z,4-dichlorobutanes.

14 Claims, No Drawings PREPARATION OF' l-SUBSTITUTED-Ii-CHLOROPYRROLIDINES This application is a continuation-in-part ofapplication Ser. No. 746,284, filed July 22, 1968, now abandoned.

A number of drugs are known which inhibit the actions of acetylcholineon structures enervated by postganglionic cholinergic nerves and onsmooth muscles that respond to acetylcholine but lack cholinergicenervation. These agents are generically known as antimuscarinic agentsand demonstrate a competitive or surmountable antagonism toacetylcholine and other muscarinic agents. In essence, these drugs caninhibit muscarinic actions of acetylcholine and other choline esters.Such drugs have also been variously termed by a number of other namessuch as anticholinergic drugs.

One particular drug of this class is known as glycopyrrolate sold underthe trade name Robinul. This drug has the following structure:

The above drug is a potent anticholinergic drug type used for thetreatment of the gastro-intestinai tract and is particularly useful inthe treatment of peptic ulcers. While it is not entirely understoodexactly how this drug works it is assumed that it behaves along the lineof the acid-peptic theory, and it is strongly felt that proper therapyis achieved through an antacid effect. The just mentioned drug isparticularly effective at extremely low concentrations, and thereforedoes not induce undesirable side effects such as dizziness,restlessness, irritability, disorientation, depression, and otherundesirable side effects, generally due to a blocking of responses toparasympathetic activity at all effector organs. Most drugs of this typeproduce the undesirable side effects of generalized parasympatheticblock.

A very important intermediate used to prepare glycopyrrolates is al-hydrocarbyl-3-chloropyrrolidine. The commercial glycopyrrolate can beprepared by reaction of l-methyl-3-chloropyrrolidine with the sodiumsalt of alpha-phenylcyclopentaneglycolic acid. The resultant compound isthen quaternized with methyl bromide to produce the commercialanti-cholinergic compound shown above.

Up to now the l-hydrocarbyl-3-chloropyrrolidines have been prepared bythe chlorination of a lhydrocarbyl-3-pyrrolidinol by reaction with suchreagents as thionyl chloride. The l-hydrocarbyl-3-pyrrolidinols areprepared only through an extremely complicated sequence of steps. Themulti-step synthesis involves a great number of individual and difficultsteps, leading to an overall poor yield of the desired 1- hydrocarbyl-3chloropyrrolidine.

It would be a considerable advance in the art if a new and simplifiedmethod of achieving a l-hydrocarbyl-3- chloropyrrolidine were found. Ifthe pyrrolidine could be made in a minimum number of steps, andparticularly could be achieved in relatively high yields withoutisolating intermediates, such process would be a distinct advance in theart.

It therefore becomes an object of the invention to provide a method ofpreparing a l-hydrocarbyl-3- chloropyrrolidine.

A specific object of the invention is to prepare the above pyrrolidinein a simplified procedure which does not involve exotic reagents orsophisticated tailor-made equipment.

Another object of the invention is to provide a method of preparing al-hydrocarbyl-3-chloropyrrolidine in relatively high yields through anintermediate which need not be isolated.

Yet another object of the invention is to provide a method of making al-hydrocarbyl-3-chloropyrrolidine from a starting material which iseasily prepared by known techniques.

A still further object of the invention is to provide novel intermediatecompounds produced in making a l-hydrocarbyl-3-chloropyrrolidine.

Other objects will appear hereinafter.

BROAD DESCRIPTION OF THE INVENTION In accordance with the invention anew procedure for making a l-hydrocarbyl-3-chloropyrrolidine has beendiscovered. In its broadest aspects the process involves effecting achloro rearrangement of an N- chloro-l-hydrocarbyl-amino-2-chlorobutaneto a lhydrocarbyl-amino-2,4-dichlorobutane. This is carried out bytreatment of the first named compound with a strongly ionized acid and afree radicalgenerating catalyst. Thel-hydrocarbyI-amino-2,4-dichlorobutane is then cyclized by treatment ofsaid dichlorobutane with a base to produce the sought-after pyrrolidinecompound. The pyrrolidine compound is then further reacted as outlinedabove to produce the desired glycopyrrolate. A number of intermediatesleading up to the desired product are believed to be novel also.

DETAILED DESCRIPTION OF THE INVENTION The first step in the reactionsequence set out here involves a chloro rearrangement of anN-chloro-lhydrocarbyl-amino-2-chlorobutane. This compound can beobtained via a number of techniques which will be described in furtherdetail hereinafter. This rearrangement is broadly effected by treatmentof the above compound with a strongly ionized acid and a catalyst whichhas the capability of generating free radicals. The treatment with acidcatalyst may be effected by a wide variety of techniques to effect therearrangement. Perhaps the best procedure is to add theN-chloro-l-hydrocarbyl-amino-2-chlorobutane to a cold solution of strongacid. In the typical situation the chlorobutane is added over a periodof time ranging from about 10 to about 60 minutes while holding thestrong acid at 0l 5 C. The acid in effect acts both as a solvent andaids in carrying out the rearrangement.

In still another embodiment of the invention a solution of thechlorobutane may be added to the cold sulfuric acid. The solventemployed, of course, must not be effected by the strongly ionized acid.One excellent solvent that may be utilized here is chloroform. Aftertreatment with acid the lower acid layer is separated from the organicsolvent layer. The upper organic layer may then be extracted a number oftimes with further portions of acid to get increased yields of thewanted product.

The acid that is employed here is a strongly ionized acid or one knownas a super acid. These acids are well-known in the art and need littleelaboration. They have a pK at 25 C. of less than 4.0. Typical amongthese are concentrated sulfuric acids such as 85 percent sulfuric acid,concentrated phosphoric acid as 85 percent phosphoric acid andtrihaloacetic acids such as trifluoroacetic acid. Other strongly ionizedacids may also be used.

Again, treatment with the appropriate catalyst may be effected in anumber of varying ways. For example, the catalyst may be added to theacid, to which combination is then added the chlorobutane. However, ithas been determined that the best mode of treatment involves firstcontact of the chlorobutane with the strong acid as elaborated above,followed by addition thereto of the catalyst. After addition of catalystit is preferred that the mixture then be heated. The heat treatment mayvary widely with respect to time and temperature variables. In a typicalsituation the mixture is heated for 1/36 hours at a temperature rangingfrom about 70 to about 120C.

The free radical generating catalyst may be an aliphatic or aromaticdiazo compound, an organic or inorganic peroxy compound, or a redoxsystem.

The diazo compound preferably is one having fewer than 20 carbons.Illustrative aliphatic diazo compounds include bisazoisobutyronitrile,bisazoisobutane, biazoisoctane, bisazoZ-caprylicnitrile anddiazomethane. Bisazoisobutyronitrile is a preferred catalyst.Illustrative aromatic diazo compounds include4,4dimethoxydiazoaminobenzene, p-methoxyphenyldiazothio-2naphthyl etherand diazoaminobenzene.

The organic peroxy compound may be any of the following:

R--OR' or R-O-OH where R and R are alkyl, aryl, alkaryl, aralkyl or acylhaving fewer than carbons. Illustrative species include diethylperoxide, dibutyl peroxide, diacetyl peroxide, dibutyryl peroxide,benzoyl peroxide, bisphenylacetyl peroxide, a-cumyl hydroperoxide,peracetic acid, perbenzoic acid and perdecanoic acid.

The inorganic peroxy compounds may be hydrogen peroxide, the metalperoxides, perborates, percarbonates, perchlorates and persulfates.Preferred metals are sodium, potassium and lithium. For the purposesherein ammonium also is regarded as a metal. Thus, ammonium persulfateis an effective catalyst. A particularly preferred catalyst is potassiumpersulfate.

The redox systems contemplated herein are combinations of any of theabove peroxy compounds with a reducing agent. The reducing agent usuallyis the ferrous ion, although it may also be a reducing sugar such asglucose or fructose, or a polyamine such as ethylene or propylenepolyamines, e.g., diethylene triamine, tetraethylene pentamine,pentapropylene hexamine and propylene diamine. The polyamines, hereinare alkylene polyamines having up to six alkylene groups where thealkylene groups may each contain up to four carbons.

' A particularly preferred catalyst system is a redox catalyst systemsuch as the combination of ferrous ammonium sulfate and potassiumpersulfate.

The above reaction may be better depicted through the followingequation:

In the above formula the R group or l-substitutent on the nitrogen atommay be rather widely varied. Preferred R groups are alkyl groups havingfrom one to l2 carbons, phenylalkyl groups having from seven to l0carbons and cycloalkyl groups having from four to eight carbons. Amongthese may be specified methyl, ethyl, butyl, isopropyl, benzyl,cyclopentyl, cyclohexyl, 4-methylcyclohexyl, cyclobutyl, etc. Preferredl-substituent groups attached to the nitrogen atom include methyl,benzyl, and cyclohexyl. Of course, if one wishes to make theglycopyrrolate known as Robinul" the substituent on the nitrogen ismethyl.

The second step in the reaction sequence involves treatment of thedichlorobutane with base to effect ring closure. This in effect leaves apyrrolidine structure having a chloro group in the three position and aR group as defined above attached to the ring nitrogen. Thel-hydrocarbyl-3-chloropyrrolidine can then be used as an intermediate inmaking a wide variety of compounds as well as in making glycopyrrolate.

The ring closure reaction is as follows:

| OH- R-NH-CHQCH-OHliCEhGI L J The ring closure reaction is best carriedout by treating the acid solvent containing the dichlorobutane with abase. Any strong base, including particularly alkali and alkaline earthmetal hydroxides, may be utilized here, and usually cooling is requiredduring the addition of the base due to the exothermic reaction involved.Thus, such basic reagents as sodium hydroxide, potassium hydroxide,lithium hydroxide, sodium carbonate, calcium hydroxide and bariumhydroxide may be utilized. Due to ready availability and low cost,sodium hydroxide is preferred. As a typical example a solutioncontaining 20-50 percent by weight of sodium hydroxide may be added tothe sulfuric acid solution. During the addition it is preferred that thetemperature be kept below about C. and more often below about 60C.

After addition of base the mixture may be warmed, if desired, and theproduct then isolated. The best means of isolating the pyrrolidine is byextraction with an appropriate organic material. In a typical run, thepyrrolidine is extracted with a number of portions of ethyl ether. Theether extracts are then dried over sodium sulfate, the ether separatedfrom the pyrrolidine by distillation under vacuum, and the sought-afterproduct thus isolated.

In the above sequence of steps it is a preferred practice that the1-hydrocarbyl-amino-2,4-dichlorobutane not be isolated, though ifdesired it could be otherwise.

There are a number of different ways to obtain theN-chloro-l-hydrocarbyl-amino-2-chlorobutane reactant as shown above.Perhaps the best method is carried out by reacting al-hydrocarbyl-amino-2- chlorobutane with a source of hypohalite orhalite. Preferred reagents here are sodium hypochlorite, sodiumchlorite, sodium hypobromite, sodium bromite, and like reagents. Sodiumhypochlorite is particularly preferred. This reaction is shown asfollows:

01 c1 or NaOCl l l R-NH-omoH-cmcm RN-CHzCH-CH2OHa This particular stepmay be carried out a number of ways. For example, an aqueous solution ofthe lhydrocarbyl-amino-2-chlorobutane or salt thereof may be preparedwhich is then added to the hypohalite or halite. As a specific example asolution of 2-chlorobutane may be added to a solution of sodiumhypochlorite. in one experiment to equal amounts of an aqueous solutionof sodium hypochlorite and chloroform was added the aqueous solution ofthe amino-chlorobutane. The chloroform or organic layer contains thedesired product of N-chloro-l-hydrocarbyl-amino-2-chlorobutane. Theaqueous layer may be then extracted with additional portions of organicextractants such as chloroform to obtain as much yield of product as ispossible.

ln following this sequence of events, that is, starting with al-hydrocarbyl-amino-2-chlorobutane to achieve thel-hydrocarbyl-3-chloropyrrolidine, neither of the two intermediates,that is, the N-chloro-l-hydrocarbylamino-2-chlorobutane and thel-hydrocarbyl-amino- 2,4-dichlorobutane need be isolated, and theoverall reaction sequence proceeds satisfactorily without doing so. Suchis a distinct advantage with respect to the overall method of theinvention, making the above sequence of steps more attractive frompractical and commercial standpoints.

Again, the l-hydrocarbyl-amino-2-chlorobutane reagent may be preparedvia a number of known reported techniques. For example, al-hydrocarbyl-amino-2-butanol may be reacted with thionyl chloride,thereby replacing the hydroxy group with a chloro group. With morespecificity, the amino butanol may be dissolved in a solvent such asbenzene to which is added a slight excess of thionyl chloride. Thereaction is then caused to occur by refluxing the benzene for a numberof hours, such as 2-3 hours. The hydrochloride of thelhydrocarbyl-amino-2-chloro-butane is then obtained which is filteredfrom the reaction mass and washed with various solvents such as benzeneand acetone. This reaction proceeds as follows:

Lastly, the l-hydrocarbyl-amino-2-butanol may be prepared by reaction ofa primary amine with butylene oxide viaa well-known type of reaction.Thus, for example, an aqueous solution of a monoalkylamine such asmethylamine, may be prepared. To this is then added l,2-epoxybutane,with the amine being employed in a molar excess such as in a 5:1 ratio.

Equal molar amounts of amine and epoxy compound may also be reactedwhereupon the reactants are heated to reflux for a period of say 3-6hours. The mixture can then be fractionally distilled to obtain thesubstituted butanol compound. In still another type of reaction anexcess of aniline may be caused to react with the epoxy butane. Again,the reaction mixture may be heated to reflux for a number of hours, sayaround 6 hours. Excess aniline is then vacuum distilled from thereaction mass and the residue containing the desired butanol compoundrecrystallized from hexane.

While a number of reactions have been discussed above, essence of theinvention lies in the discovery that through use of a particular acidand catalyst a specific chloro rearrangement may be effected asdemonstrated above. The second phase of the essential part of theinvention lies in treating the thus chloro rearranged derivative withbase to effect the appropriate ring closure.

The following examples illustrate typical ways of carrying out themethod of the invention. It is understood, of course, that theseexamples are merely illustrative, and that the invention is not to belimited thereto. All parts and percentages are by weight unlessotherwise expressed.

EXAMPLE I PREPARATION OF l-METHYL-3- CHLOROPYRROLIDINE A solution of15.8 g. (0.1 mole) of l-methylamino-Z- butyl chloride hydrochloride in60 ml. of water was added to a stirring ice cold mixture of 150 ml. of al N sodium hypochlorite solution and 150 ml. of chloroform over a 20minute period. The temperature during addition was kept below 10C. Thechloroform layer was then separated from the aqueous layer, and theaqueous layer extracted twice with IS ml. portions of chloroform. Thecombined chloroform solution of N-chloro-l-methylamino-2-chloro-butanewas chilled in an ice bath and added with stirring to 60 ml. of ice coldpercent sulfuric acid over a 20-30 minute period at 5-l0C. The lowersulfuric acid layer was then separated from the chloroform layer, andthe chloroform layer was then extracted twice with 20 ml. portions of 85percent sulfuric acid. To the combined 85% sulfuric acid solution wasadded 0.4 g. of ferrous ammonium sulfate and 0.2 g. of potassiumpersulfate. The catalyst-treated mixture was heated to l05-l 10 C. untila drop of the mixture added to about 2-3 ml. of a l-2 percent potassiumiodide solution no longer liberated free iodine (development of a yellowto red color). This required approximately 1.5 hours. The solution wasthen cooled and added to a cold solution of 200 g. of sodium hydroxidein 500 ml. of water at such a rate that the temperature did not exceed60C. The mixture was then warmed to 60C. for 10 minutes, cooled andextracted with six 50 ml. portions of ethyl ether. The ether extractswere dried over sodium sulfate, and then the ether was distilled off ona hot water bath. The residual from the ether distillation was thenvacuum-distilled to give 4.4 g. (37 percent) oflmethyl-3-chloropyrrolidine. The pyrrolidine had a b.p.

of 80C. at 120 mm. pressure. lts l.R. spectrum was compared with a knownsample of 1-methyl-3- chloropyrrolidine prepared by reaction of thionylchloride with l-methyl-3-pyrrolidinol. The l.R. spectrum of the sampleprepared in this experiment was identical with that prepared accordingto the prior art technique.

EXAMPLE ll PREPARATION OF l-BENZYL-3- CHLOROPYRROLIDINE A solution of23.4 g. (0.1 mole) of 1-benzylamino-2- butylchloride hydrochloride in100 ml. of water was added with stirring toa mixture of 150 ml.chloroform and 150 ml. of 1 N sodium hypochlorite solution over a 20minute period at 5-l0C. The chloroform layer was separated and theaqueous layer extracted twice with 25 ml. portions of chloroform. Thecombined chloroform solution was chilled in an ice bath and added withstirring to 60 ml. of cold 85 percent sulfuric acid over a 30 minuteperiod at 5-10C. The lower layer of sulfuric acid solution was separatedfrom-the chloroform layer. The chloroform layer was extracted twice with60 ml. portions of 85 percent sulfuric acid. To the combined 85 percentsulfuric acid solution of N-chloro-lbenzylamino-2-chlorobutane was added0.3 g. of ferrous ammonium sulfate and 0.3 g. of potassium persulfate.The mixture was heated to 55- 60C. for 1.5 hours, cooled and added to astirring solution of 300 g. of sodium hydroxide contained in 700 ml. ofwater at such a rate that the internal temperature did not exceed 60C.The mixture was kept at 60C. for -15 minutes and cooled. The product wasextracted with five 100 ml. portions of ethyl ether. Distillation of theethereal extracts yielded 6.2 g. (32.2%) of lbenzyl-3-chloropyrrolidine,b.p. of 9296C./l mm. The LR. spectrum was the same as that of anauthentic sample (prepared from l-benzyl-3-pyrrolidinol and thionylchloride).

EXAMPLE lII PREPARATION OF l-CYCLOHEXYL-3- CHLOROPYRROLIDINE A solutionof 23.4 g. (0.1 mole) of l-cyclohexylamino-2-butyl chloridehydrochloride was added with stirring to a cold mixture of 150 ml. 1 Nsodium hypochlorite and 150 ml. of chloroform over a minute period at5-l0C. The chloroform layer was separated and the aqueous layerextracted twice with ml. portions of chloroform. The cold combinedchloroform solution was added with stirring to 60 ml. of cold 85 percentsulfuric acid over a minute period at 10C. The 85 percent sulfuric acidsolution was separated from the chloroform which was extracted twicewith 30 ml. portions of 85 percent sulfuric acid. To the combined 85percent sulfuric acid solution of N-chloro-l-cyclohexyl-amino-2-chlorobutane was added 0.3 g. of ferrousammonium sulfate and 0.3 g. of potassium persulfate. An exothermicreaction occurred at this point and the temperature rose to C. It wasmaintained at this point for 1.5 hours, after which time littleunreacted material was left. By heating up to 80C. all traces of activechloride-containing substance were removed. The 85 percent sulfuric acidsolution was then chilled, and added with stirring to a cold solution of250 g. of sodium hydroxide contained in 600 ml. of water at such a ratethat the temperature did not exceed 60C. Then the mixture was kept at60C. for 15 minutes, cooled and extracted 5 times with ml. portions ofethyl ether. Distillation of the ethereal extracts yielded 13.6 g. (72.5percent yield) of l-cyclohexylamino-3-chloropyrrolidine, b.p. of72-75C./1 mm.

IMPORTANCE OF CATALYST This example illustrates the importance ofutilization of catalyst in order to obtain reasonably satisfactoryyields.

EXAMPLE [V Essentially the directions of Example I was followed with theexception that the ferrous ammonium sulfate and potassium persulfateredox catalyst combination was not employed. The percent sulfuric acidsolution of N-chloro-l-methyl-amino-2-chlorobutane had to be heated for4 hours instead of the 1.5 hours heating step in Example 1 in order forthe reaction to be completed (evidenced by no liberation of iodine inthe potassium iodide solution). After processing in an identical manner,only 2.4 g. (20 percent yield) of lmethyl-3-chloropyrrolidine wasobtained.

It is thought that a number of intermediates employed to gain thedesired l-hydrocarbyl-3-chloropyrrolidine are new. These include thel-hydrocarbylamino-2-chlorobutanes,N-chloro-l-hydrocarbylamino-2-chlorobutanes and l-hydrocarbyl-amino-2,4-dichlorobutanes, where the l-hydrocarbyl or R group is as beforedefined.

The above products of the invention found as intermediates in theherewith disclosed process may be utilized for a wide variety ofpurposes. Of course, these products are intermediates toward preparationof the sought-after glycopyrrolate when R is methyl. Similar derivativesof this type may be used for preparation of drugs exhibiting a varietyof therapeutic effects. Moreover, the claimed compounds may be used asintermediates in forming a wide variety of organic substances useful innumerous industrial applications. For example, from these compounds maybe made corrosion inhibitors, antifoams, polymeric substances of diversetypes useful as coagulants, as paper additives, etc., vulcanizationaccelerators, herbicides, pesticides, scale inhibitors in evaporators,feed water heaters, economizers, boilers and other parts of steamgenerating systems, microbiocides, antifoulant chemicals, surfactants,coating agents, chemical adjuvants used in treatment of textiles forvarious purposes, etc. The compounds discovered here may be used notonly to prepare derivatives for the just-mentioned uses and others, butin many instances may be directly used for these purposes withoutfurther chemical modification or formulation.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodification, and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within know or customary practice in the artto which the invention pertains and as may be applied to the essentialfeatures hereinbefore set forth, and as fall within the scope of theinvention.

What is claimed is:

l. A method for preparing l-hydrocarbyl-3- chloropyrrolidines whichcomprises the steps of effecting rearrangement of anN-chloro-l-hydrocarbylamino-2-chlorobutane to a l-hydrocarbyl-amino-2,4-dichlorobutane by treatment with a strongly ionized acid having a pKless than 4 and a free radical generating catalyst, followed bytreatment of said dichlorobutane with an alkali or alkaline earth metalbase, said hydrocarbyl group being an alkyl group having from one to 12carbons, a phenylalkyl group having from seven to carbons or acycloalkyl group having from four to eight carbons.

2. The method of claim 1 wherein the hydrocarbyl group is an alkylgroup.

3. The method of claim 2 wherein the strongly ionized acid isconcentrated sulfuric, concentrated phosphoric, or a trihaloacetic acid.

4. The method of claim 3 wherein the strongly ionized acid isconcentrated sulfuric.

5. The method of claim 3 wherein the strongly ionized acid isconcentrated phosphoric acid.

6. The method of claim 2 wherein the hydrocarbyl group is methyl.

7. The method of claim 2 wherein the hydrocarbyl group is benzyl.

8. The method of claim 2 wherein the hydrocarbyl group is cyclohexyl.

9. The method of claim 1 wherein the base is sodium hydroxide. I

10. The method of claim 2 wherein the base is sodium hydroxide.

11. The method of claim 3 wherein the base is sodium hydroxide.

12. The method of claim 1 wherein said catalyst is a redox catalyst.

13. The method of claim 1 wherein said catalyst is hydrogen peroxide.

14. The method of claim 11 wherein said redox catalyst comprises ferrousammonium sulfate and potassium persulfate.

2. The method of claim 1 wherein the hydrocarbyl group is an alkylgroup.
 3. The method of claim 2 wherein the strongly ionized acid isconcentrated sulfuric, concentRated phosphoric, or a trihaloacetic acid.4. The method of claim 3 wherein the strongly ionized acid isconcentrated sulfuric.
 5. The method of claim 3 wherein the stronglyionized acid is concentrated phosphoric acid.
 6. The method of claim 2wherein the hydrocarbyl group is methyl.
 7. The method of claim 2wherein the hydrocarbyl group is benzyl.
 8. The method of claim 2wherein the hydrocarbyl group is cyclohexyl.
 9. The method of claim 1wherein the base is sodium hydroxide.
 10. The method of claim 2 whereinthe base is sodium hydroxide.
 11. The method of claim 3 wherein the baseis sodium hydroxide.
 12. The method of claim 1 wherein said catalyst isa redox catalyst.
 13. The method of claim 1 wherein said catalyst ishydrogen peroxide.
 14. The method of claim 11 wherein said redoxcatalyst comprises ferrous ammonium sulfate and potassium persulfate.